review article role of uric acid metabolism-related...

Review ArticleRole of Uric Acid Metabolism-Related Inflammation inthe Pathogenesis of Metabolic Syndrome Components Such asAtherosclerosis and Nonalcoholic Steatohepatitis

Akifumi Kushiyama,1 Yusuke Nakatsu,2 Yasuka Matsunaga,2

Takeshi Yamamotoya,2 Keiichi Mori,2 Koji Ueda,2 Yuki Inoue,2 Hideyuki Sakoda,3

Midori Fujishiro,4 Hiraku Ono,5 and Tomoichiro Asano2

1Division of Diabetes and Metabolism, Institute for Adult Disease, Asahi Life Foundation, 1-6-1 Marunouchi,Chiyoda-ku, Tokyo, Japan2Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi,Minami-ku, Hiroshima City, Hiroshima, Japan3Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine,University of Miyazaki, Miyazaki 889-1692, Japan4Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan5Department of Endocrinology and Diabetes, School of Medicine, Saitama Medical University, Moroyama, Saitama 350-0495, Japan

Correspondence should be addressed to Akifumi Kushiyama; [email protected]

Received 18 September 2016; Revised 3 November 2016; Accepted 15 November 2016

Academic Editor: Jie Yin

Copyright © 2016 Akifumi Kushiyama et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Uric acid (UA) is the end product of purine metabolism and can reportedly act as an antioxidant. However, recently, numerousclinical and basic research approaches have revealed close associations of hyperuricemia with several disorders, particularly thosecomprising themetabolic syndrome. In this review, we first outline the twomolecularmechanisms underlying inflammation occur-rence in relation to UA metabolism; one is inflammasome activation by UA crystallization and the other involves superoxide freeradicals generated by xanthine oxidase (XO). Importantly, recent studies have demonstrated the therapeutic or preventive effects ofXO inhibitors against atherosclerosis and nonalcoholic steatohepatitis, which were not previously considered to be related, at leastnot directly, to hyperuricemia. Such beneficial effects of XO inhibitors have been reported for other organs including the kidneysand the heart. Thus, a major portion of this review focuses on the relationships between UA metabolism and the developmentof atherosclerosis, nonalcoholic steatohepatitis, and related disorders. Although further studies are necessary, XO inhibitors are apotentially novel strategy for reducing the risk of many forms of organ failure characteristic of the metabolic syndrome.

1. Introduction

Uric acid (UA) is the end product of the metabolic path-way for purines, the main constituents of nucleotides. Thepathway of UA generation is shown in Figure 1. Briefly,inosine monophosphate (IMP) is derived from de novopurine synthesis and from purine salvage. Hypoxanthinefrom IMP is catalyzed to xanthine and then to uric acid byxanthine oxidase (XO). De novo nucleotide synthesis gener-ates IMP via ribose-5-phosphate, catalyzed to 5-phosphor-ibosyl-1-pyrophosphate (PRPP). In the salvage pathway,

hypoxanthine-guanine phosphoribosyl transferase (HGPRT)plays an important role in generating IMP, thereby inhibitingUA generation.

Since humans are unable to catabolize UA to the moresoluble compound allantoin due to lack of urate oxidase oruricase [1], the serum UA concentration is higher in humansthan almost all other mammals. However, this high UA levelin humans has been regarded as being beneficial in thepresence of elevated oxidative stress [2]. UA is oxidized toallantoin and other metabolites via nonenzymatic oxidation

Hindawi Publishing CorporationMediators of InflammationVolume 2016, Article ID 8603164, 15 pageshttp://dx.doi.org/10.1155/2016/8603164

2 Mediators of Inflammation

UA metabolic route

Purine intake

Purinedegradation

De novo pathway

ATP

Alcohol intake Insulin

Glucose Glycogen

−ATP−ATP

Glucose 6-phosphate

Ribose 5-phosphate

Fructose intake

Fructose

Fructose −ATP6-phosphate

−ATPPRPP synthetase

Phosphoribosyl diphosphate (PRPP)ATPase

ADP GMP

Glyceraldehyde3-phosphate

GDP GTP

Adenine Adenosine Inosine Guanosine

Hypoxanthine Guanine

Xanthine oxidase Xanthine

Uric acid

Allantoin

Allantoic acid

Salvage pathway

Glyoxylic acid + urea

TG accumulation

AMP IMP

Figure 1: Metabolic pathways involving UA.

[3] and, thus, UA can function to neutralize prooxidantmolecules, such as hydroxyl radicals, hydrogen peroxide,and peroxynitrite. UA shows the highest scavenging rateconstant against O2

−∙, with constants being low againstCH3∙ and t-BuOO∙ [4]. UA directly (nonenzymatically)and preferentially deletes nitric oxide (NO) and forms 6-aminouracil in physiological environments or in associationwith antioxidants [5]. In vitro, UA has both an antioxidanteffect on native LDL and a prooxidant effect on mildlyoxidized LDL [6]. Allantoin does not have these effects. Themechanisms of these reactions vary among combinations ofprooxidant molecules and solution polarities [7].

It has been suggested that this antioxidant effect of thehigh UA concentrations in humans contributes to neuropro-tection in several neurodegenerative and neuroinflammatorydiseases [8–14].

However, despite the potential antioxidant effect of UAitself, numerous studies have revealed close associations ofserum UA concentrations and various disorders, most ofwhich are included in themetabolic syndrome category.Thus,UA metabolism may be a so-called double-edged sword asregards the inflammatory and/or oxidative responses inmanyorgans, though on the whole, its harmful effects appear tooutweigh the benefits of UA in most cases.

In this review, we first explain the two putative molecularmechanisms underlying inflammation occurrence in relationto UA metabolism; one is inflammasome activation via UA

crystallization and the other involves superoxide free radicalsgenerated by XO. While the UA crystallization mechanismwould be dependent on a high serum UA concentration, thelatter may not necessarily reflect the serumUA concentrationthough XO activity does lead to the production of reactiveoxygen species (ROS).

Subsequently, lines of research showing relationshipsbetween UA metabolism and the development of variousdisorders are introduced and discussed. Importantly, recentstudies have demonstrated beneficial effects of XO inhibitorsagainst the occurrence and/or progression of several dis-orders, particularly atherosclerosis and nonalcoholic steato-hepatitis (NASH), both of which are associated with insulinresistance, hyperlipidemia, and/or obesity. In this review,atherosclerosis and NASH are discussed extensively, whilestudies of gout and chronic kidney diseases (CKD) arementioned briefly. In conclusion, we propose that such XOinhibitors may be more useful for preventing a variety ofdisorders, such as atherosclerosis and NASH, than previouslybelieved, probably via an anti-inflammatory effect.

2. Inflammation Occurrence Related toUA Metabolism

Among the disorders related to hyperuricemia, gout is themost representative and well known. Features of gout includepainful arthritis affecting the limbs, caused by reduced UA

Mediators of Inflammation 3

crystals in the joints. While symptoms of a gout attack aretypical of an acute inflammatory response, as indicated bythe presence of swelling, heat, rubescence, and pain, thereare many disorders with mild but chronic inflammationwhich are very likely to be related to UA metabolism. In thelatter case, superoxide free radicals generated by XO are keyplayers leading to chronic inflammatory processes eventuallyresulting in impaired organ functions. Thus, we introducetwo independent mechanisms underlying UA metabolism-induced inflammation.

2.1. Inflammasome Activation by Crystallized UA Particles. In2002, the inflammasome concept was proposed to involvemultiple proteins and to control the cleavage of prointer-leukin 1 (IL-1) [15]. Initially, inflammasomes were consideredto play a role in immune responses and serve as defense sys-tems against pathogens [16, 17]. However, a line of subsequentstudies has elucidated that inflammasomes are key players inthe onsets of a wide range of diseases as well as host defense.Excessive metabolites, such as ATP or monosodium uratecrystals (MUC), were also confirmed to be involved in theactivation of inflammasomes, and inflammatory responsesoccurring via inflammasomes have been demonstrated tobe linked to the onset and progression of human diseases,including gout, atherosclerosis and NASH, as describedbelow in detail [18–24].

Inflammasomes are known to be divided into dis-cernible patterns, depending on component proteins [16].Among them, the NLRP3 inflammasome, comprised of threemajor components, Nod-like receptor 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC) andcaspase-1, has beenwell investigated.Maturations of both IL-1and IL-18 by inflammasomes require a two-step mechanism.First, the Toll-like receptor ligands, such as lipopolysaccha-ride (LPS), activate the NF-𝜅B pathway and upregulate theexpression levels of interleukins, including pro-IL-1𝛽 andpro-IL-18. Subsequently, the inflammasome complex acti-vated by pathogen-associated molecular patterns (PAMPs)or damage-associated molecular patterns (DAMPs) cleavespro-IL-1𝛽 or pro-IL-18, resulting in the production of matureinterleukins [15–17].

MUC also reportedly serve as a danger signal and triggerthe activation of inflammasomes [18]. Although the mech-anism of inflammasome activation by MUC has not beenfully elucidated, the following mechanism was proposed.MUC stimulate the Toll-like receptor 2/4-Myd88 pathwayand raise transcriptional levels of pro-IL-1𝛽 through theNF-𝜅B pathway [25]. It is theorized that MUC-inducedinflammasome activation is driven by two key factors. Oneis a decrease in the intracellular potassium concentration.Indeed, the addition of high potassium abrogated IL-1𝛽release by MUC.The other is the generation of ROS, becausean antioxidant, N-acetyl-cysteine, abolished IL-1𝛽 secretionby MUC [26]. Other studies have indicated the applicationof MUC to raise intracellular ROS levels. However, therelationship between intracellular K+ level changes and ROSgeneration remains unknown, and future studies are expectedto resolve this issue [27, 28]. Elevation of intracellular ROSmediates the detachment of thioredoxin-interacting protein

(TXNIP) from thioredoxin and enables TXNIP to associatewith NLRP3, leading to NLRP3 inflammasome activation[29, 30]. Thus, MUC accumulation promotes inflammatoryresponses through inflammasomes (Figure 2) and therebypromotes the onset of diseases, such as gout.

2.2. Superoxide Free Radicals Generated by XO. When mam-malian xanthine dehydrogenase (XDH) is converted to XOunder stressed conditions such as tissue damage and ischemia[31], superoxide anion and hydrogen peroxide are producedduring molybdenum hydroxylase-catalyzed reactions in amolar ratio of about 1 : 3 [32]. The proteolytic activationfrom XDH to XO is required for superoxide generation [33].In essence, XO oxidizes a variety of purines and pterins,classified as molybdenum iron-sulfur flavin hydroxylases.When XO reacts with xanthine, electrons are transferredfrom Mo, Fe-S, and FAD. XO produces FADH2, while XDHproduces FADH. Only FADH2 reacts with O2 [34]. In theUA metabolic pathway, XO oxidizes hypoxanthine fromnucleic acid metabolites into xanthine and xanthine intoUA (Figure 1). XO, as well as nicotinamide adenine dinu-cleotide phosphate (NADPH) oxidase and the mitochondrialelectron-transport chain, generates ROS [35].

ROS fromXOmight play physiological roles, especially indevelopment. Treatment during pregnancy with allopurinolalters maternal vascular function involving 𝛽1-adrenergicstimulation and impairs the fetal 𝛼1-adrenergic vasoreflexresponse involving NO [36]. Fetal XO is activated in vivoduring hypoxia and XO-derived ROS contributes to fetalperipheral vasoconstriction, leading to fetal defense againsthypoxia [37]. XO depletion induces renal interstitial fibrosis,and renal epithelial cells from XOR (−/−) mice are morereadily transformed into myofibroblasts [38]. Indeed, howROS from XO directly and physiologically acts in vivo isunknown.

The tissue and cellular distributions of XO in mammalsare highest in the liver and intestines due to XO-richparenchymal cells [39]. Xanthine oxidoreductase (XOR) ispresent in hepatocytes, while XO is present in bile ductepithelial cells, concentrated toward the luminal surface.Moreover, in human liver disease, proliferating bile ducts arealso strongly positive for XO [40]. Molybdenum supplemen-tation significantly increased XO activities in the liver andsmall intestinal mucosa [41]. XO activity is low in humanserum, the brain, heart, and skeletal muscle, while being richin microvascular endothelial cells [42] and is also present inmacrophages [43]. Circulating XO can adhere to endothelialcells by associating with endothelial glycosaminoglycans[44]. The study using electron spin resonance measure-ments revealed the contribution of increased XO activityto endothelial dysfunction in patients with coronary arterydiseases [45].

XO activation is induced by LPS, angiotensin II, NADPHoxidase, hypoxia, hypoxia-inducible factor 1, and inflamma-tory cytokines such as IL-1𝛽 [46–49]. The release of XO isincreased in hypercholesterolemia, chronic hyperammone-mia, thermal trauma, beta-thalassemia, brain ischemia, andpulmonary artery hypertension [50–54]. Aging is anotherfactor associated with elevated XO activity. Indeed, XO was


MUC

MUC

ROS

TXNIP

TRX

NLRP3

ASC

Caspase-1

MUC

TLR

p65p50Pro-IL-1𝛽

TXNIP

IL-1𝛽

NADPH oxidase

?K+

K+

Figure 2: MUC induces inflammasome activation. MUC activates the NF-𝜅B pathway through TLR2/4, thereby increasing the expressionsof pro-IL-1𝛽 or pro-IL-18. At the same time, MUC induces ROS release from mitochondria. The generated ROS detaches TXNIP fromthioredoxin and enables TXNIP to interact with the NLRP3 complex. The binding of TXNIP to NLRP3 activates inflammasomes, leading tothe production of mature IL-1𝛽 or IL-18. MUC: monosodium urate crystals, TLR: Toll-like receptor, TXNIP: thioredoxin-interacting protein,TXR: thioredoxin, and ROS: reactive oxygen species.

significantly higher in the aortic walls and skeletal musclesof old rats than in those of their young counterparts. Thecorrelation between plasma XO activity and age is observedin both humans and rats [55]. It appears that hyperglycemiaitself has no impact on liver XO activity, though cardiac,renal, and brain XO activities were shown to be increasedin rats with advanced diabetes [56, 57]. XO activity risesremarkably in ischemic congestive heart failure and XOlocalizes within CD68 positive macrophages [43]. The asso-ciation between XO and ischemic reperfusion injury hasbeen well investigated. XO is one of the major superoxidesources in ischemia/reperfusion injuries of the heart [58],forebrain [59], skin [60], liver [61, 62], and gastric mucosa[63], as well as multiple system organ failure after hind limbreperfusion [64]. XO activity, along with lipid peroxidation,myeloperoxidase activity and NO levels, is increased in theliver in response to renal ischemia/reperfusion in diabetic rats[65]. Ischemia/reperfusion injury is attributable to elevatedXO activity and ATP depletion related to increasing hypox-anthine and xanthine levels during ischemia, and reperfusionprovides O2 for oxidation of these compounds [1].

Superoxide production by XO may also be enhancedby increasing the amount of its substrate, purine bodies.Excess fructose metabolism results in ATP depletion whichis associated with degradation of AMP to hypoxanthine,followed by conversion to UA by XO [66]. Indeed, theserum UA level is upregulated in response to a fructoseburden [67]. Inversely, UA stimulates fructokinase and fruc-tose metabolism during fatty liver development [68]. ATP

depletion, such as that characteristic of glycogen storagedisease type 1 [69], hypoglycemia [70], exercise [71], andstarvation [72], also increases UA production. Conditionsassociated with DNA turnover, such as tumor progression[73] and tumor lysis [74], are also mediated by XO.

Superoxide produced by XO is an important messengerinducing inflammation and signal transduction, leading totissue damage. We found inflammatory cytokines to beinduced via XO when foam cells form with lipid accu-mulation [75]. XO regulates cyclooxygenase-2 [76] in theinflammatory system, and XO appears to be critical forinnate immune function [77]. XO increased Egr-1 mRNAand protein, as well as the phosphorylation of ERK1/2, whilepretreatment with an ERK1/2 inhibitor prevented inductionof Egr-1 by XO [78]. In addition, XO reportedly reducedSUMOylation of PPAR𝛾 in inflammatory cells [79]. ROSfrom XO augment TRB3 expression in podocytes [80].

As noted above, superoxide from XO has been suggestedto play roles in various forms of inflammatory or ischemicpathophysiology (Figure 3), not necessarily involving hyper-uricemia.

3. UA Metabolism and Chronic Renal Disease,Atherosclerosis, Heart Failure, and NASH

While gout is a disorder well known to be caused by the pre-cipitation of UA crystals, the involvement of hyperuricemiain CKD is also widely recognized. The major causes of CKDhave been regarded as diabetes mellitus and hypertension,


ROS

NADPH

LPS

TLR

?

XO

Tissue damage/ ischemic condition

Angiotensin IIInflammatory cytokinesIL-1𝛽 etc.)

Lipid

Mo

?

?

Lipid accumulation

Inflammation

Cox-2

Egr-1

Uric acid

Purine metabolism

ERK1/2 P

ERK1/2

JNK

JNK P

Lipidtransporter

Cytokinesreceptor

XDH

XDH

receptor

Cidea

C/EBP

Oxidative stress

XDH

Insulin resistance

PPAR SUMO

Hypoxia

XDHHIF-1

PPAR

ER stress

[O2] ↓AT2

𝛾

𝛾

and so on

Figure 3: Involvement of XO in molecular pathologies related to inflammation; “causes and results.”

and thus, hyperuricemia was long viewed as a consequence ofCKD. In fact, loss of kidney function reduces the excretion ofUA into urine, resulting in hyperuricemia. In contrast, recentstudies demonstrated a significant association between serumUA and the development of CKD. While each metabolicsyndrome component, including hyperglycemia, hyperlipi-demia, and hypertension, was associated with an increasedCKD risk, hyperuricemia was apparently an independent riskfactor not influenced by the others.Therefore, hyperuricemiais both a cause and a consequence of CKD and is frequentlyassociated with other metabolic syndrome features.

In terms of CKD pathogenesis, serum UA is likely toactivate the renin-angiotensin system resulting in vascularsmooth muscle cell proliferation [81] and to induce anepithelial-to-mesenchymal transition of renal tubular cells[82]. XO inhibitor treatment reportedly reduced intercel-lular adhesion molecule-1 (ICAM-1) expression in tubularepithelial cells [83] of mice. We speculate that UA itself

and superoxide free radical generation both play rolesin the molecular mechanisms underlying hyperuricemia-related CKD development, but further research is requiredto elucidate the complex mechanistic interactions betweenserum UA and CKD.

As mentioned in Section 2, both UA and superoxide freeradicals are simultaneously produced by XO and might bethe pathophysiological cause of these diseases. As shown inFigure 3, chronic inflammation is also involved in pathophys-iological processes, generally exhibiting a close relationshipwith oxidative stress. ROS from XO induces LPS-inducedJNK activation via inactivation of MAPK phosphatase-(MKP-) 1 [84] and XO regulates cyclooxygenase-2, one ofthe master regulators of inflammation [76]. Therefore, dam-age from UA, ROS, and UA-induced and/or ROS-inducedinflammation might together contribute to the progressionof certain diseases, and distinguishing whichmechanism actsfirst is often difficult in lifestyle-related diseases.


3.1. Atherosclerosis, Vascular Dysfunction, and Heart Failure.Although the relationships between serum UA levels andatherosclerotic diseases, including hypertension [85, 86],have been documented, whether or not serum UA itself is anindependent cardiovascular risk factor remains controversialas most hyperuricemic patients with cardiovascular diseases(CVD) have other complications such as hypertension, dys-lipidemia, diabetes, and CKD as well, which are generallyregarded as more established risk factors for CVD than hype-ruricemia. Recently, however, a growing body of evidencefrom both clinical and basic research supports the hypothesisthat hyperuricemia, partly via elevated XO activity, is anindependent risk factor for hypertension and CVD.

Despite the association between hyperuricemia andhypertension having been recognized since the 19th cen-tury [85], it was not until recently that hyperuricemia wasdemonstrated to be an independent risk factor for hyper-tension development [87–93]. A recently published meta-analysis showed that the adjusted relative risk of developinghypertension was 1.48 for hyperuricemic patients [94], andthis association was apparently much stronger in younger,early-onset hypertensive patients [86, 95]. Several clinicaltrials have demonstrated the beneficial effects of UA low-ering therapy for hypertension [96–99]. In a trial targetingprehypertensive obese adolescents, administration of eitherallopurinol (XO inhibitor) or probenecid (uricosuric agent)lowered blood pressure [98]. Consistently, both allopurinoland benziodarone (uricosuric agent) reduced blood pressurein rats with hypertension induced by hyperuricemia [100,101], suggesting that not only XO activity but also UA itselfplays an important role in the pathogenesis of hypertension.

Besides the associationwith hypertension, hyperuricemiaor gout has been confirmed to be related to the morbidityand the mortality of CVD [102–106]. According to a recentlypublished meta-analysis [107], the relative risks of morbidityand mortality for coronary heart diseases were 1.13 and1.27, respectively, in hyperuricemic patients as compared tocontrols. Several clinical studies have indicated the benefitsof XO inhibitors for reducing the incidence of myocardialinfarction [108], improving exercise tolerance in patientswith stable angina [109], and enhancing endothelial function[110, 111]. However, interestingly, unlike the case of treatinghypertension, uricosuric agents have failed to show anybenefits in patients with hyperuricemia or gout [110, 112].

What are themechanisms underlying the aforementionedassociation between hyperuricemia and atherosclerotic dis-eases? First, the role of XO in the pathogenesis of atheroscle-rosis merits attention. As described above, XO produces ROSwhen converting hypoxanthine into xanthine and then UA.XO is also expressed in endothelial cells [113] and was shownto be increased in the aortic endothelial cells of ApoE−/−mice[114], an established model of atherosclerosis. Since oxidativestress inactivates NO and leads to endothelial dysfunction[115], endothelial XO, especially given its enhanced expres-sion during the development of atherosclerosis, contributesto vascular damage via ROS production.

Recently, we established that XO activity in macrophagesalso plays a key role in the development of atherosclerosis[75].During atherosclerosis development,monocytesmigrate

beneath the endothelium and transform into macrophages,which then turn into foam cells by incorporating modi-fied low density lipoproteins (LDL) (such as oxidized LDLand acetyl LDL) or very low density lipoproteins (VLDL).Foam cells contribute to the formation of unstable plaquesby secreting inflammatory mediators and matrix-degradingproteases (such as matrix metalloproteinases (MMPs)) andby generating a prothrombotic necrotic core by eventuallyundergoing necrotic or apoptotic death [116]. We demon-strated that allopurinol treatment ameliorated aortic lipidaccumulation and calcification of the vessels of ApoE-KOmice and that allopurinol markedly suppressed the transfor-mation of J774.1 murine macrophages or primary culturedhuman macrophages into foam cells in response to stimula-tion with acetyl LDL or VLDL. The expressions of scavengerreceptors (SR-A1, SR-B1, and SR-B2) and VLDL receptorsin J774.1 cells were upregulated by XOR overexpression anddownregulated by siRNA-mediated XOR suppression, raisingthe possibility that XO activity in macrophages positivelyregulates foam cell formation by increasing the uptake ofmodified LDL or VLDL. Conversely, expressions of ABCA1and ABCG1, which regulate cellular cholesterol efflux, weredecreased by XOR overexpression and increased by XORknockdown. Furthermore, allopurinol suppressed the expres-sions of inflammatory cytokines such as IL-1𝛽, IL-6, IL-12, and TNF𝛼, and the expressions of VCAM1, MCP-1, andMMP2, which were upregulated in J774.1 cells transformedinto foam cells by atherosclerogenic serum. Subsequently,febuxostat, another XO inhibitor, was also demonstratedto attenuate the development of atherosclerotic lesions inApoE−/− mice [114]. That study showed XO expressionto be increased in macrophages infiltrating atheroscleroticplaques and that febuxostat diminished the ROS level in theaortic walls of ApoE−/− mice. The authors demonstrated thatcholesterol crystals (CCs) increased endogenous XO activityand ROS production in macrophages and that CCs enhancednot only IL-1𝛽 release via NLRP3 inflammasome activationbut also secretions of other inflammatory cytokines such asIL-1𝛼, IL-6, and MCP-1 from macrophages, processes whichin turn were suppressed by febuxostat or ROS inhibitors.The significance of NLRP3 inflammasome activation inmacrophages by CCs was verified by the observation thatatherosclerosis in high-cholesterol diet fed LDL receptor-(LDLR-) deficient mice was alleviated by transplanting bonemarrow from NLRP3-deficient, ASC-deficient, or IL-1𝛼/𝛽-deficient mice [117]. Taking these observations together, wecan reasonably speculate that XO in macrophages enhancesfoam cell formation, ROS production, andNLRP3 inflamma-some activation, all three of which exacerbate inflammationand plaque formation, thereby contributing to the develop-ment of atherosclerotic diseases [75, 114–116].

Independently of XO, UA itself is widely recognized toexert direct effects on vascular functions. Vascular endothe-lial cells express several UA transporters [118] and incorpo-rated UA impairs NO production and leads to endothelialdysfunction [118, 119]. In vascular smooth muscle cells, UAstimulates proliferation andROS production and inhibits NOproduction via increased angiotensin II expression [81, 120].As noted above, not only XO inhibitors but also uricosuric


agents markedly lowered blood pressure, especially in studiestargeting early-stage hypertensive patients [98] and thoseusing animal models [100, 101]. The results obtained suggestthat UA presumably contributes to early-stage hypertensionby promoting renal vasoconstriction via reducedNOproduc-tion and activation of the renin-angiotensin system [86, 98].

3.2. Nonalcoholic Steatohepatitis. The number of nonalco-holic fatty liver disease (NAFLD) patients including thosewith NASH has been increasing worldwide and a portionof NASH patients will progress to hepatocarcinoma onset[121–123]. Therefore, numerous investigations have beenperformed in efforts to elucidate the causes of NASH.

NASH is characterized by fat deposition, inflammationand fibrosis in the liver, and a two-hitmechanism of onset hasbeen proposed [124–126]. This hypothesis is that fatty liverformation and subsequent injuries, including inflammationand oxidative stress, cause NASH pathology [127]. Interest-ingly, recent studies have raised the possibility that UA isamong the risk factors for NASH pathology. We discuss therelationship between UA and NASH below.

3.2.1. Serum UA Is a Predictor of NAFLD/NASH Onset andProgression. Many clinical studies have been carried out toinvestigate the relationship between serum UA levels andNAFLD/NASH progression. For example, a cohort studyin Korea found the serum UA level to be a useful markerfor predicting NAFLD development because the serum UAconcentration correlated positively with the 5-year incidencerate of NAFLD [128]. Their conclusion is supported byanother study showing that serum UA levels of NAFLDpatients are higher than those of control groups [129]. Inaddition, there are also studies demonstrating that serumUAis a risk factor for the development and/or progression ofNAFLD including NASH [130–132].

Consistent with these observations, hepatic XO activitiesand serum UA levels are reportedly increased in murineNAFLD/NASH models [133, 134]. Moreover, a fraction ofNAFLD/NASH patients also have obesity, and hypertrophicadipocytes were also reported to secrete UA [135]. Takentogether, these results indicate serumUA to be a good param-eter for predicting the development of NAFLD/NASH, andthat XO inhibitors or uricosuric agents might have potentialas treatments for ameliorating the features of NAFLD.

3.2.2. The Mechanism of UA-Induced NAFLD/NASH Pro-gression. As described above, increasing serum UA or XOactivity apparently plays important roles in NAFLD/NASHonset and progression. Interestingly, UA was reported toinduce fat depositions by enhancing lipogenesis in hepato-cytes. Fructose treatment ofHepG2 cells reportedly increasedboth the intracellularUA concentration and triglyceride (TG)accumulation, while allopurinol, an XO inhibitor, suppressedthis fructose-mediated TGdeposition.Moreover, the applica-tion of UA alone was demonstrated to increase intracellularTG contents as well as ROS generation in mitochondria[136]. As a mechanism of UA-induced TG accumulation, theauthors asserted that the elevation of intracellular ROS byUA raised both the citrate concentration and ATP citrate

lyase activity via enhanced phosphorylation at S455, resultingin the induction of lipogenesis. These observations are sup-ported by those of another study in which pretreatment withantioxidants inhibited the elevation of triglyceride contentsby UA [137].The authors asserted that ROS generation by UAevoked endoplasmic reticulum stress, leading to upregulationof lipogenic genes, such as acetyl CoA carboxylase1 and FASN[137].

ROS generation by UA is considered to depend onNADPH oxidase activation [136, 138, 139]. For example, UAreportedly promotes translocation of the NADPH oxidasesubunit NOX4 into mitochondria [136]. It was also reportedthat UA treatment raises NADPH oxidase activity and altersits localization, leading to lipid oxidation [139]. In addition,XOmay also function as a source of ROS generation becauseXO activity is upregulated in the livers of murine NASHmodels.

Collectively, these observations indicate thatUAenhancesfatty acid synthesis by regulating lipogenesis and inducesROS generation by regulating NADPH oxidase activity andupregulating fatty acid synthesis, thereby contributing toNASH development.

3.2.3. Inflammasome Participation in NASH Progression.As described elsewhere, UA is involved in inflammasomeactivation. Recent investigations have provided convincingevidence that inflammasomes are key players inNASHdevel-opment. An initial study revealed that inflammasome impair-ment exacerbated the NASH progression induced by feedinga methionine-choline deficient diet for 4 weeks to ASC orIL-1 KO mice [140]. Subsequent studies, however, found thatinflammasomes themselves exacerbateNASH symptoms. Forexample, it was reported that NLRP3 deficiency prevents liverfibrosis in response to a choline diet deficient in amino acids[141]. In addition, caspase-1 deficient mice were also resistantto developing steatosis or fibrosis while being fed a high-fatdiet [142]. Moreover, other groups have demonstrated thatdiets which lead to NASH also increase the expressions ofinflammasome components [143–145].

Taking these lines of evidence together, in the initial stageof NASH, inflammasomes appear to exert a protective effect,but continuous inflammasome activation appears to causeexcessive productions of inflammatory cytokines, ultimatelyresulting in liver injury. Although, to date, numerous factorsplaying important roles in NASH progression have beenidentified, UA also appears to be a key participant in the onsetof NAFLD/NASH.

3.3. Insulin Resistance, Diabetes, and Hyperlipidemia. Hype-ruricemia was reportedly found to be related to insulinresistance in several clinical analyses [146–152]. In addition,several meta-analyses have suggested the UA level to bepositively associated with the development of type 2 diabetesmellitus (DM) [153–156], althoughMendelian randomizationstudies did not support circulating UA as being among thecauses of DMdevelopment [157, 158]. Inmetabolic syndromepatients, an oxidative stress marker, the myeloperoxidaselevel, was decreased by allopurinol and endothelial functionimproved [159]. On the other hand, rapid UA reduction


Infection

Ischemia

Excess energy intake

Fructose intake

Exercise

Starvation

Low oxygenation

Tumor lysis

Immune response

Lipid accumulation

Purine intake

ATP depletion

Purine generation

ADP

ATP

Uric acid

Purine

Ribose-5-phosphate and so on

Purine

XO activity ↑

XO substrate ↑

Alcohol intake

Figure 4: Increased catalyst activity of XO, originating from pathological and physiological events. Involvement of XO in pathophysiologicalprocesses suggests applications of XO inhibitors to the treatment of various disorders.

achieved by rasburicase, a urate oxidase, in obese subjectswith high UA resulted in increasing the markers of systemicand skeletal muscle oxidative stress while having no effect oninsulin sensitivity [160].

Furthermore, excess fructose intake is one of the majorcauses of the development of obesity with hyperuricemia,fatty liver, and metabolic syndrome. Fructose is metabo-lized by fructokinase to fructose-1-phosphate and resultsin a drop in both intracellular phosphate and ATP levels[161]. The intracellular phosphate decrease stimulates AMPdeaminase (AMPD), the enzyme catalyzing the degradationof AMP to inosine monophosphate and eventually UA.Activated AMPD increases the expressions of gluconeo-genesis genes, that is, PEPCK and G6Pase, via inhibitionof AMP-activated protein kinase (AMPK) [162]. AMPDalso increases lipogenesis through AMPK inhibition. AMPKphosphorylation was decreased in HepG2 cells treated withUA. The UA increased fructose-induced TG accumulationand decreased 𝛽-hydroxybutyrate levels, dose-dependently,while allopurinol, a XO inhibitor, blocked it. Because UAis the downstream product of AMPD and allopurinol abol-ished fructose-induced lipid accumulation, AMPD effectson AMPK appeared to depend on UA [163]. UA activatesthe transcription factor ChREBP, which triggers a viciouscycle of fructokinase transcription and accelerated fructosemetabolism [68]. Via these mechanisms, activated AMPDand increased UA production tend to promote fat accumu-lation and glucose production.

UA is considered to be an antioxidant in human blood,though UA induces oxidative stress in cells [164]. UA raisedNADPH oxidase activity and ROS production in matureadipocytes. The stimulation of NADPH oxidase-dependentROS by UA resulted in the activation of MAP kinase p38and ERK1/2, a decrease in NO bioavailability, and increasesin both protein nitrosylation and lipid oxidation [138].Increased UA production, in turn, generates mitochondrialoxidants. Mitochondrial oxidative stress inhibits aconitase inthe Krebs cycle, resulting in citrate accumulation and the

stimulation of ATP citrate lyase and fatty acid synthase, ulti-mately leading to de novo lipogenesis [136]. In hepatocytestreated with high UA, oxidative stress is increased, whichactivates serine (rat Ser307 and human Ser312) phosphory-lation of IRS-1. This activity impairs Akt phosphorylation,thereby resulting in acute hepatic insulin resistance afterexposure to highUA levels [165].Therefore, UA-induced lipidaccumulation and oxidative stress are responsible for thedevelopment of insulin resistance and diabetes.

4. Beneficial Effects of XO InhibitorsInvolvement of increased XO catalyst activity in patho-physiological processes (Figure 4) suggests applications ofXO inhibitors to the treatment of various disorders. Atpresent, XO inhibitors, including allopurinol, oxypurinol,febuxostat, and topiroxostat, are widely used for treating goutand hyperuricemia. Furthermore, XO inhibitors have beenexperimentally or clinically shown to exert beneficial effectsby lowering serum UA and oxidative stress.

Febuxostat preserved renal function in 5/6 nephrec-tomized rats with and without coexisting hyperuricemiaand prevented diabetic renal injury in streptozotocin-treatedrats [166, 167]. Febuxostat also ameliorated tubular dam-age, diminished macrophage interstitial infiltration, andsuppressed both proinflammatory cytokine activities andoxidative stress [168]. Febuxostat also reduced the inductionof endoplasmic reticulum stress, as assessed by GRP-78(glucose-regulated protein-78), ATF4 (activating transcrip-tion factor-4), and CHOP (C/EBP homologous protein-10)[169]. The clinical significance of measuring the serum UAlevel and XO inhibition for renal protection has largely beenestablished by the results of recent studies [170–173].

On the other hand, beneficial effects of XO inhibitorson atherosclerosis and NASH constitute an evolving conceptthat has yet to be proven. In rats with fructose-inducedmetabolic syndrome, febuxostat treatment reversed hyper-uricemia, hypertension, dyslipidemia, and insulin resistance[174]. The beneficial effects of XO inhibitors on NASH are


rarely reported, except by our research group [134], becauseanimal models of NASH with obesity, inflammation, andfibrosis have been difficult to establish. NASH in responseto the MCD diet, as used in our studies, caused primarilyinflammation and also made the mice lean, such that nobenefit of XO inhibition was obtained [134]. Thus, we nextused a high-fat diet containing trans-fatty acids and a high-fructose diet to induce NASH development in our animalmodels. Another report showed that inhibition of XO activityalso significantly prevents hepatic steatosis induced by a high-fat diet in mice. XO has also been indicated to regulateactivation of the NLRP3 inflammasome [175].

Atherosclerosis has been far more extensively investi-gated than NASH, both clinically and experimentally. Tung-sten, acting as an XO inhibitor, has an inhibitory effect onboth atherosclerosis and oxidative stress [176]. We reportedfor the first time that more specific XO inhibition, usingallopurinol rather than tungsten onmacrophages, resulted inthe inhibition of foam cell formation and reduced atheroscle-rotic lesions in ApoE-KO mice, independently of the serumlipid profile [75]. We also identified phenotypic changes ofmacrophages in response to allopurinol, such as alterations ofgene expressions involved in lipid accumulation. Moreover,both XO overexpression and knockdown of XO expressionrevealed VLDL receptors to be dramatically upregulatedby XO. Febuxostat was also proven to have similar effectsin terms of reducing the atherosclerotic lesions in ApoE-KO mice, and oxidative stress was reduced in macrophagesfrom atherosclerotic lesions [113]. Febuxostat also suppressedLPS-induced MCP-1 production via MAPK phosphatase-1-mediated inactivation of JNK [84]. As a strategy for suppress-ing atherosclerosis, XO inhibition is expected to act on eithermacrophages or inflammatory cells.

XO inhibitors also improve endothelial function and pre-vent vascular remodeling. Oxypurinol reduces O2

− radicaldot production and improves endothelial function in bloodvessels from hyperlipidemic experimental animals [69].XO inhibition can also provide protection from radiation-induced endothelial dysfunction and cardiovascular com-plications [177]. Allopurinol treatment prevents hypoxia-induced vascular remodeling in the lung [178]. However,controversy persists as to whether the effect of XO onendothelial function is clinically relevant as an interventionaltarget [49]. Pretreatment with XO inhibitors has beneficialeffects on ischemia/reperfusion injuries of the intestine [179],in the impaired liver [61, 62], the edematous brain [180],kidneys with contrast induced nephropathy [181], and coro-nary ischemia [182]. XO inhibitors prevent postischemic O2

−

generation [183].

5. Conclusion

Inflammation related to UA metabolism is induced viaeither inflammasome activation by UA crystal precipitationor free radical production in response to XO activity. Inaddition to gout, many disorders are known to be relatedto UA metabolism and XO inhibitor treatments have beenshown to be effective for preventing the onset and/or theprogression of such disorders. In particular, atherosclerosis

and NASH are diseases for which relationships with UAmetabolism were not immediately recognized, but rodentmodel studies revealed the importance of UA metabolismmaintenance for managing these disorders. We believe theimpact of UA metabolism on many diseases accompanyingchronic inflammation to have been underestimated. Futurestudies are anticipated to reveal the pathological contributionof serum UA and/or XO activity to the specific processesunderlying various disorders. Further study of the detailedmolecular mechanisms is clearly warranted.

Abbreviations

UA: Uric acidMUC: Monosodium urate crystalNASH: Nonalcoholic steatohepatitisXO: Xanthine oxidaseLPS: LipopolysaccharideTIMP: Tissue inhibitor of metalloproteinasesMCP-1: Monocyte chemoattractant protein 1NADPH: Nicotinamide adenine dinucleotide phosphateCKD: Chronic kidney diseaseICAM-1: Intercellular adhesion molecule-1.

Competing Interests

The authors have no competing interests regarding thepublication of this report to declare.

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